This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aggregation of Abeta peptides is a major contributor to Alzheimer's disease. Oligomeric forms of these peptides are especially interesting due to their high neurotoxicity and potentially important role in disease progression. However, very little structural information is currently available on Abeta oligomers. We have previously established that Abeta oligomers can be divided into at least two structural classes (prefibrillar and fibrillar oligomers) based on their reactivity with conformational antibodies. Here we compared both site-specific and global conformational stability of Abeta 40 fibrils and both classes of oligomers. To measure the site-specific stability, we introduced cysteine residues throughout the sequence of Abeta 40, labeled the new cysteines with the fluorescent dye acrylodan, and investigated their environment within the aggregates in guanidine thiocyanate-induced denaturation experiments. We found that Abeta 40 fibrils show high stability towards denaturation and moderate hydrophobicity in the 15-35 region with the exception of residues 25-30. This pattern is consistent with previously published structures of Abeta 40 fibrils. Fibrillar oligomers show similar pattern consistent with our hypothesis that they represent fragments of protofibrils. However, prefibrillar oligomers show lower stability towards denaturation and more hydrophobic environment throughout the 15-35 region of the peptide. Distinct conformational properties of prefibrillar oligomers may explain their differential recognition by conformational antibodies and serve as a basis for their neurotoxicity.